Abstract: Tuberculosis (TB) kills nearly two million people annually. Long treatment regimens result in patient non-compliance, and the consequent development of drug-resistance. The HIV/AIDS pandemic has further hastened the emergence of extensively drug-resistant (XDR) strains that are both lethal and transmissible. New therapeutic approaches are urgently needed. Existing anti-TB therapies target the bacteria. This project will exploit my recent discoveries about host susceptibility to TB to develop novel therapeutic strategies based on targeting specific, genetically-determined host immune pathways. Through a large-scale forward genetic screen in the zebrafish I identified the leukotriene A4 hydrolase (lta4h) gene as critical in controlling susceptibility to TB. In fish and in mammals, the LTA4H enzyme functions as a rheostat, controlling relative levels of specific pro- and anti- inflammatory eicosanoids. We found that common LTA4H polymorphisms in human populations control susceptibility to TB and leprosy. People with LTA4H genotypes that result in intermediate levels of inflammation are protected from TB. Intriguingly, individuals with LTA4H genotypes that maximize pro-inflammatory responses fared just as poorly as those with genotypes resulting in inadequate inflammation. These findings suggest an entirely new paradigm in our understanding of TB susceptibility. People are hypersusceptible for two diametrically opposed reasons - an inadequate response to the infection or an overexuberant hyperinflammatory response that is equally detrimental to the host. This proposal will explore the hypothesis that host-directed therapies personalized to common genotypes will provide a fundamentally new approach to combating TB. In strong support of my hypothesis, I have found that human LTA4H genotypes determine clinical responsiveness to standard adjunctive therapy for TB meningitis. We will use the zebrafish model to understand the repercussions of these hypo- and hyperinflammatory states for TB pathogenesis and disease outcome. We will examine drugs that specifically target host eicosanoid pathways as an entirely new avenue of anti-TB treatment. Lastly, the modeling of hypo- and hyperinflammatory states will provide a platform for whole animal, in vivo screening for new drugs that target host eicosanoid pathways. Public Health Relevance: This proposal aims to develop new approaches to treating tuberculosis, a disease that kills nearly two million people annually and is estimated to infect one third of the world's population. The tailoring of effective adjunctive therapies based on patient genotype could have immediate impact on the treatment of TB meningitis, a particularly deadly form of the disease.